EP1461040B1 - Sels succiniques de 5,8,14-triazatetracyclo 10.3.1.02,11.0 4,9 -hexadeca-2(11),3,5,7,9-pentaene et compositions pharmaceutiques associees - Google Patents

Sels succiniques de 5,8,14-triazatetracyclo 10.3.1.02,11.0 4,9 -hexadeca-2(11),3,5,7,9-pentaene et compositions pharmaceutiques associees Download PDF

Info

Publication number
EP1461040B1
EP1461040B1 EP02775143A EP02775143A EP1461040B1 EP 1461040 B1 EP1461040 B1 EP 1461040B1 EP 02775143 A EP02775143 A EP 02775143A EP 02775143 A EP02775143 A EP 02775143A EP 1461040 B1 EP1461040 B1 EP 1461040B1
Authority
EP
European Patent Office
Prior art keywords
compound according
ray diffraction
diffraction pattern
triazatetracyclo
pentaene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP02775143A
Other languages
German (de)
English (en)
Other versions
EP1461040A1 (fr
Inventor
George J. Pfizer Global Rch. and Dev. QUALLICH
Lewin Theophilus Wint
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
Original Assignee
Pfizer Products Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of EP1461040A1 publication Critical patent/EP1461040A1/fr
Application granted granted Critical
Publication of EP1461040B1 publication Critical patent/EP1461040B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems

Definitions

  • the present invention is directed to the succinate salts of 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof.
  • the succinate salts can take an anhydrous form or a hydrated form.
  • the compound 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene, binds to neuronal nicotinic acetylcholine specific receptor sites and is useful in modulating cholinergic function.
  • This compound is useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.g.
  • AD Alzheimer's type
  • PD Parkinson's disease
  • ADHD attention deficit hyperactivity disorder
  • Tourette's Syndrome Tourette's Syndrome.
  • the succinate salts of this invention may also be used in a pharmaceutical composition in combination with an antidepressant such as, for example, a tricyclic antidepressant or a serotonin reuptake inhibiting antidepressant (SRI), in order to treat both the cognitive decline and depression associated with AD, PD, stroke, Huntington's chorea or traumatic brain injury (TBI); in combination with muscarinic agonists in order to stimulate both central muscarinic and nicotinic receptors for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD, stroke, Huntington's chorea and TBI; in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD stroke, Huntington's chorea and TBI; or in combination with agents that slow or arrest AD such as cognition enhancers, amyloid aggregation inhibitors, secretase inhibitors,
  • the succinate salts of the present invention exhibits properties, including those of solid-state stability and compatibility with certain drug product formulation excipients, that render it preferable among known salts of 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 -hexadeca-2(11),3,5,7,9-pentaene. Further, the succinate salt formation is an extremely efficient means of purifying 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 -hexadeca-2(11),3,5,7,9-pentaene.
  • the present invention relates to the succinate salt of 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 -hexadeca-2(11),3,5,7,9-pentaene.
  • the present invention relates to the anhydrous and hydrate forms of this succinate salt.
  • Particularly preferred is the anhydrous succinate salt.
  • Another embodiment of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the succinate salt of 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene and a pharmaceutically acceptable carrier or excipient, particularly, one for use in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritablebowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction,anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy,
  • Another more preferred embodiment of the invention is wherein the pharmaceutical composition above is useful in the treatment of nicotine dependency, addition and withdrawed, most preferably for use in smoking cessation therapy.
  • the present invention further relates to the use of the succinate salt of 5,8,14-triazatetracyclo [10.3.1.0 2,11 .0 4,9 ]-hexadica-2(11),3,5, 7,9-pentaene for the manufacture of a medicament useful for treating inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritablebowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction,anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.g.
  • Another more preferred embodiment of the invention relates to said use for the manufacture of a medicament useful in the treatment for nicotine dependency, addiction and withdrawed, in particular for use in smoking cessation therapy activity.
  • the invention also relates to a process for the preparation of the anhydrous succinate salt of 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene comprising the steps of
  • the suitable solvent is selected from the group consisting of a (C 1 -C 6 )alkyl alcohol, a (C 1 -C 6 )alkyl ketone or a (C 1 -C 8 )alkyl ether in the presence of water. More preferably, the suitable solvent is acetone or 2-propanol. Most preferably, the suitable solvent is 2-propanol.
  • the process of the invention is wherein the contacting of step (i) is carried out by contacting 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene in solution phase with a solution of succinic acid.
  • the contacting step is carried out over a period of between 1 and 24 hours, more preferably between 5 and 15 hours, and comprising stirring or mixing the resulting mixture.
  • a preferred embodiment of the process is wherein step (i) is run between ambient temperature and the refluxing temperature of the solvent; more preferably, between ambient temperature and the refluxing temperature of 2-propanol, i.e., about 80 °C; most preferably, the process in run between 30 and 60 °C.
  • the compound, 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene is a nicotinic partial agonist for the treatment of a number of CNS diseases, disorders and conditions including, in particular, nicotine dependency, addiction and withdrawal.
  • the succinate salts of 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 -hexadeca-2(11),3,5,7,9-pentaene are only slightly hygroscopic and have high aqueous solubility. These characteristics make the succinate salt highly suitable for pharmaceutical formulation use.
  • the anhydrous succinate salt of the present invention exhibits a hygroscopicity of approximately 1.97% wt/wt on exposure to 90% relative humidity in a moisture chamber.
  • the aqueous solubility of the anhydrous succinate salt is 442 mg/ml.
  • anhydrous succinate salt of 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene exhibits excellent solid state stability both in light and elevated temperatures as well as high humidity challenges.
  • the aqueous solubility of the anhydrous succinate salt has been measured under various conditions: > 10 mg/mL in pH 4 buffer, > 10 mg/mL in pH 10 buffer; > 10 mg/mL in 0.1 N HCl; and > 10 mg/mL in 0.1 N NaOH.
  • the solubility of the anhydrous succinate salt has also been measured in various solvents: > 10 mg/mL in methanol; 0.1 mg/mL in acetonitrile and ⁇ 0.01 mg/mL in hexane.
  • the hygroscopicity of the anhydrous succinate salt has also been measured under various conditions: 0.0% moisture gain at 20% Relative Humidity; 0.3% moisture gain at 40% Relative Humidity; 0.6% moisture gain at 60% Relative Humidity; 0.9% moisture gain at 80% Relative Humidity and 1.3% moisture gain at 95% Relative Humidity.
  • the anhydrous succinate salt has been prepared under different conditions via dissolving 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene in acetone or 2-propanol and then added to a succinic acid solution also in acetone. A slurry is formed and allowed to stir at 20 to 25 °C for approximately 24 hours. The product crystallizes on agitation to give the desired anhydrous salt usually in high yield. The product crystals are small and generally agglomerated or aggregated together.
  • the hydrate salt can be formed via the use of a water containing solvents, i.e., 50:50 mixtures of acetone or 2-propanol.
  • the solid state thermal behavior of the succinate salt of the invention was investigated by differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • the trace for the anhydrous succinate salt is shown in Figure 2; the hydrate succinate salt in Figure 4.
  • the DSC thermogram was obtained on a Mettler Toledo DSC 821 e (STAR e System). Generally, samples between 1 and 10 mg were prepared in crimped aluminum pans with a small pinhole. The measurements were run at a heating rate of 5 °C per minute in the range of 30 to 300 °C.
  • the anhydrous succinate salt exhibits onset of melt transition at about 198 °C (more precisely measured at 197.8 °C).
  • the succinate salt hydrate exhibits tow solid-solid transitions with onsets at about 70 °C and about 144 °C, and an onset of melt transition at about 191°C (more precisely measured at 190.9 °C).
  • DSC measurement there is a certain degree of variability in actual measured onset and peak temperatures which occur depending on rate of heating, crystal shape and purity, and other measurement parameters.
  • the anhydrous succinate salt is characterized in that it forms prism-shaped crystals and has an onset of melting transition point at about 198 °C as measured by differential scanning calorimetry (DSC). Further, the anhydrous succinate salt of the invention is also characterized in having an aqueous solubility of 442 mg/ml and a native pH of 4.7 in aqueous solution. In addition, the anhydrous succinate salt has a hygroscopicity of approximately 1.97 % at 90% relative humidity.
  • the power x-ray diffraction patterns for the succinate salt of the invention was collected using a Bruker D5000 diffractometer (Bruker AXS, Madison, Wisconsin) equipped with copper radiation CuK ⁇ , fixed slits (1.0, 1.0, 0.6 mm), and a Kevex solid state detector. Data was collected from 3.0 to 40.0 degrees in two theta (2 ⁇ ) using a step size of 0.04 degrees and a step time of 1.0 seconds.
  • the x-ray powder diffraction pattern of the succinate salts were conducted with a copper anode with wavelength 1 at 1.54056 and wavelength 2 at 1.54439 (relative intensity: 0.500).
  • the range for 2 ⁇ was between 3.0 to 40.0 degrees with a step size of 0.04 degrees, a step time of 1.00 second, a smoothing width of 0.300 and a threshold of 1.0.
  • Table I The diffraction peaks at diffraction angles (2 ⁇ ) in the measured powder X-ray diffraction analysis for the anhydrous succinate salt are shown in Table I. The relative intensities, however, may change depending on the crystal size and morphology. The actual measured powder diffractogram is displayed In Figure 1. Table I. Powder X-ray Diffraction Pattern for with intensities and Peak Locations of Diffraction Lines. Angle 2 ⁇ d-value ( ⁇ ) I (rel.) 6.5 13.5 38% 13.1 6.7 100 16.5 5.4 49 17.0 5.2 78 19.8 4.5 63 22.2 4.0 79 23.8 3.7 77
  • Table II sets forth the 2 ⁇ and the d-spacings for the highest relative intensities for the powder x-ray diffraction pattem. Table II. Powder X-ray Diffraction Intensities and Peak Locations for Anhydrous Succinate Salt. Angle 2 ⁇ d-value ( ⁇ ) I (rel.) 13.1 6.7 100 17.0 5.2 78 22.2 4.0 79 23.8 3.7 77
  • Table IV sets forth the 2 ⁇ and the d-spacings for the highest relative intensities for the powder x-ray diffraction pattern of the hydrate succinate salt. Table IV. Powder X-ray Diffraction Intensities and Peak Locations for the Succinate Salt Hydrate. Angle 2 ⁇ d-value ( ⁇ ) I (rel.) 13.0 6.8 73 16.5 5.4 74 19.4 4.6 100
  • the succinate salts of the invention can be administered via either the oral, transdermal (e.g. , through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred.
  • An active salt can, most desirably, administered in dosages ranging from about 0.01 mg up to about 1500 mg per day, preferably from about 0.1 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.001 mg to about 10 mg per kg of body weight per day is most desirably employed.
  • Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • an active salt can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, an active salt can be administered in a wide variety of different dosage forms, e.g., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, an active salt is present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium succinate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • a solution of an active salt in either sesame or peanut oil or in aqueous propylene glycol can be employed.
  • the aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • a 200 ml reactor was charged with the free base 5,8,14-triazatetracyclo [10.3.1.0 2.1 .0 4,9 ]-hexadeca-2(11),3,5,7,9-pentaene (9 g; 0.047 mol) and 2-propanol (90 ml, 10ml/g).
  • the mixture was warmed to 50 to 55 °C to give a solution.
  • the mixture was filtered to remove any specks and fibers present.
  • the clarified solution (at 50 to 55 °C) was treated with a clarified solution of succinic acid (7.1 g., 0.0598 mol, 1.4 equiv.) dissolved in 2-propanol (36 ml) over about 5 to 15 minutes.
  • the mixture was stirred at 50 to 55°C for about 1 hour allowing crystallization to occur.
  • the crystal slurry was cooled to 0 to 5 °C over about 1 hour and the final slurry was stirred for about 1 hour.
  • the product was isolated by filtration, washed with 2-propanol (18 ml) and dried at 20 to 30°C under vacuum for about 24 hours.
  • a reactor was charged with the anhydrous succinate salt prepared in Example 1 and water(500 mL). The suspension was stirred at about 40 C for about 12 hours. The crystalline product was filtered and dried in vacuum to afford the succinate hydrate salt.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Child & Adolescent Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des sels succiniques de 5,7,13-triazatétracyclo[9.3.1.02,10.04,8]-pentadéca-2(10),3,5,8-tétraène et des compositions pharmaceutiques qui les contiennent. Elle concerne aussi un procédé de préparation de ces sels.

Claims (11)

  1. Sel de succinate de 5, 8,14-triazatétracyclo [10.3.1,02,11.04,9]-hexadéca-2(11),3,5,7,9-pentaène.
  2. Composé selon la revendication 1, le sel étant anhydre.
  3. Composé selon la revendication 2 possédant un spectre de diffraction des rayons X principalement caractérisé par des pics de diffraction des rayons X tels que mesurés avec une raie du cuivre d'un 2θ d'environ 13,3 et 17,2.
  4. Composé selon la revendication 2 possédant un spectre de diffraction des rayons X principalement caractérisé par les principaux pics de diffraction des rayons X suivants exprimés en termes de 2θ et d'espacements d tels que mesurés avec une raie du cuivre : Angle 2θ Valeur d (Å) 13,1 6,7 17,0 5,2 22,2 4,0 23,8 3,7
  5. Composé selon la revendication 2 caractérisé par un début de transition fusion/décomposition à environ 198°C.
  6. Composition pharmaceutique comprenant un composé selon la revendication 2 et un support pharmaceutiquement acceptable.
  7. Composé selon la revendication 1, le sel étant un hydrate.
  8. Composé selon la revendication 7 possédant un spectre de diffraction des rayons X principalement caractérisé par des pics de diffraction des rayons X tels que mesurés avec une raie du cuivre d'un 2θ d'environ 13,0, 16,5 et 19,0.
  9. Composé selon la revendication 7 possédant un spectre de diffraction des rayons X principalement caractérisé par les principaux pics de diffraction des rayons X suivants exprimés en termes de 2θ et d'espacements d tels que mesurés avec une raie du cuivre : Angle 2θ Valeur d (Å) 13,0 6,8 16,5 5,4 19,4 4,6
  10. Utilisation d'un composé selon la revendication 1 pour la fabrication d'un médicament utile pour traiter les maladies inflammatoires de l'intestin (incluant, sans s'y limiter, la rectocolite hémorragique, la pyodermite gangréneuse et la maladie de Crohn), le syndrome de l'intestin irritable, la dystonie spasmodique, la douleur chronique, la douleur aiguë, la maladie coeliaque, la pouchite, la vasoconstriction, l'anxiété, les troubles paniques, la dépression, les troubles bipolaires, l'autisme, les troubles du sommeil, les symptômes du décalage horaire, la sclérose latérale amyotrophique (SLA), les dysfonctionnements cognitifs, l'hypertension, la boulimie, l'anorexie, l'obésité, les arythmies cardiaques, l'hypersécrétion d'acide gastrique, les ulcères, le phéochromocytome, la paralysie musculaire progressive, les dépendances chimiques et les toxicomanies (par ex., les dépendances envers et les toxicomanies à la nicotine (et/ou aux produits du tabac), à l'alcool, aux benzodiazépines, aux barbituriques, aux opioïdes ou à la cocaïne), les céphalées, la migraine, l'accident vasculaire cérébral, les traumatismes crâniens (TC), les troubles obsessionnels compulsifs (TOC), les psychoses, la chorée de Huntington, la dyskinésie tardive, l'hyperkinésie, la dyslexie, la schizophrénie, la démence vasculaire, le déclin cognitif lié à l'âge, l'épilepsie, y compris le petit mal épileptique, la démence sénile de type Alzheimer (AD), la maladie de Parkinson (MP), les troubles d'hyperactivité avec déficit d'attention (THADA) et le syndrome de Tourette.
  11. Utilisation d'un composé selon la revendication 1 pour la fabrication d'un médicament utile pour le traitement de la dépendance envers, de la toxicomanie à ou du sevrage de la nicotine chez un mammifère.
EP02775143A 2001-11-29 2002-10-21 Sels succiniques de 5,8,14-triazatetracyclo 10.3.1.02,11.0 4,9 -hexadeca-2(11),3,5,7,9-pentaene et compositions pharmaceutiques associees Expired - Lifetime EP1461040B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US33424501P 2001-11-29 2001-11-29
US334245P 2001-11-29
PCT/IB2002/004380 WO2003045394A1 (fr) 2001-11-29 2002-10-21 Sels succiniques de 5,8,14-triazatetracyclo'10.3.1.0<2,11>.0<4,9>-hexadeca-2(11),3,5,7,9-pentaene et compositions pharmaceutiques associees

Publications (2)

Publication Number Publication Date
EP1461040A1 EP1461040A1 (fr) 2004-09-29
EP1461040B1 true EP1461040B1 (fr) 2006-03-15

Family

ID=23306297

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02775143A Expired - Lifetime EP1461040B1 (fr) 2001-11-29 2002-10-21 Sels succiniques de 5,8,14-triazatetracyclo 10.3.1.02,11.0 4,9 -hexadeca-2(11),3,5,7,9-pentaene et compositions pharmaceutiques associees

Country Status (26)

Country Link
US (1) US6794388B2 (fr)
EP (1) EP1461040B1 (fr)
JP (1) JP4196829B2 (fr)
KR (1) KR20040066140A (fr)
CN (1) CN1589148A (fr)
AR (1) AR037677A1 (fr)
AT (1) ATE320256T1 (fr)
AU (1) AU2002341327A1 (fr)
BR (1) BR0214559A (fr)
CA (1) CA2468705A1 (fr)
DE (1) DE60209929T2 (fr)
DO (1) DOP2002000512A (fr)
ES (1) ES2258652T3 (fr)
GT (1) GT200200236A (fr)
HN (1) HN2002000332A (fr)
IL (1) IL161326A0 (fr)
MX (1) MXPA04003192A (fr)
PA (1) PA8559401A1 (fr)
PE (1) PE20030738A1 (fr)
PL (1) PL374325A1 (fr)
RU (1) RU2004116311A (fr)
SV (1) SV2004001413A (fr)
TW (1) TW200300345A (fr)
UY (1) UY27548A1 (fr)
WO (1) WO2003045394A1 (fr)
ZA (1) ZA200402720B (fr)

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL136727A0 (en) * 1997-12-31 2001-06-14 Pfizer Prod Inc Aryl fused azapolycyclic compounds
DK1628685T3 (da) 2003-04-25 2011-03-21 Gilead Sciences Inc Antivirale phosphonatanaloge
WO2004103372A1 (fr) * 2003-05-20 2004-12-02 Pfizer Products Inc. Compositions pharmaceutiques a base de varenicline
ATE517622T1 (de) * 2003-10-27 2011-08-15 Merck Sharp & Dohme Salz eines tetrahydropyranylcyclopentyltetrahydropyridopyr diderivats als ccr-2 antagonisten
US7871991B2 (en) 2004-07-27 2011-01-18 Gilead Sciences, Inc. Phosphonate analogs of HIV inhibitor compounds
US20110086086A1 (en) * 2005-07-26 2011-04-14 Pfizer Inc Transdermal system for varenicline
KR100734147B1 (ko) * 2005-07-29 2007-07-02 주식회사 엘지데이콤 호 알림 지연을 통한 멀티미디어 통화연결음 서비스 시스템및 방법
JP5544165B2 (ja) * 2006-05-16 2014-07-09 ギリアード サイエンシーズ， インコーポレイテッド 血液悪性疾患の処置のための方法および組成物
AU2007319951A1 (en) * 2006-11-09 2008-05-22 Pfizer Products Inc. Polymorphs of nicotinic intermediates
PL2125786T3 (pl) * 2006-12-21 2011-07-29 Pfizer Prod Inc Bursztynian 2-((4-(1-metylo-4-(pirydyn-4-ylo)-1h-pirazol-3-ilo)fenoksy)metylo)chinoliny
WO2009109651A1 (fr) * 2008-03-06 2009-09-11 Medichem, S.A. Sels d'un dérivé de pyrazino[2,3-h][3]benzazépine
EP2268639A2 (fr) 2008-05-22 2011-01-05 Teva Pharmaceutical Industries Ltd. Tosylate de varénicline, un intermédiaire dans le procédé de préparation du l-tartrate de varénicline
US20090318460A1 (en) * 2008-05-26 2009-12-24 Glenmark Amorphous varenicline tartrate and process for the preparation thereof
MX2011000306A (es) * 2008-07-08 2011-03-15 Gilead Sciences Inc Sales de compuestos inhibidores de hiv.
US20100010221A1 (en) * 2008-07-10 2010-01-14 Revital Lifshitz-Liron Processes for purifying varenicline l-tartrate salt and preparing crystalline forms of varenicline l-tartrate salt
WO2010033045A1 (fr) * 2008-09-16 2010-03-25 Igor Anatolievich Pomytkin Compositions et procédés pour la prévention ou le traitement d’un dépôt bêta-amyloïde
ES2536558T3 (es) * 2008-12-11 2015-05-26 Cti Biopharma Corp. Sal citrato de 11-(2-pirrolidin-1-il-etoxi)-14,19-dioxa-5,7,26-triaza-tetraciclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-deceno
CA2801842A1 (fr) 2009-06-10 2010-12-16 Actavis Group Ptc Ehf Co-precipites amorphes de tartrate de varenicline
WO2010151524A1 (fr) 2009-06-22 2010-12-29 Teva Pharmaceutical Industries Ltd Formes solides des sels de varénicline et leurs procédés de préparation
WO2011140431A1 (fr) 2010-05-06 2011-11-10 Teva Pharmaceutical Industries Ltd. Sels de la varénicline et leurs formes cristallines
EP2837632B1 (fr) 2012-04-13 2016-05-18 Lianyungang Jinkang Hexin Pharmaceutical Co. Ltd. Dérivés de triazabicyclo[3.2.1]octane utiles dans le traitement de maladies proliferatives
WO2016064759A1 (fr) 2014-10-20 2016-04-28 Oyster Point Pharma, Inc. Méthodes de traitement de troubles oculaires
WO2017177024A1 (fr) 2016-04-07 2017-10-12 Oyster Point Pharma, Inc. Méthodes de traitement de troubles oculaires
EP3960740B1 (fr) 2017-08-01 2023-11-15 Gilead Sciences, Inc. Formes crystallines de vanillate de ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)méthyl)(phénoxy)phosphoryl)-l-alaninate éthyilique (gs-9131) pour le traitement d'infections virales
WO2018154395A2 (fr) 2018-06-11 2018-08-30 Alvogen Malta Operations (Row) Ltd Composition pharmaceutique à libération contrôlée de varénicline

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL136727A0 (en) * 1997-12-31 2001-06-14 Pfizer Prod Inc Aryl fused azapolycyclic compounds
EP1212085B1 (fr) 1999-08-27 2007-10-31 INEX Pharmaceuticals Corp. Compositions stimulant la secretion de cytokine et provoquant une reaction immunitaire
TWI236930B (en) * 2000-05-26 2005-08-01 Pfizer Prod Inc Reactive crystallization method to improve particle size

Also Published As

Publication number Publication date
MXPA04003192A (es) 2004-07-27
DE60209929T2 (de) 2006-11-16
HN2002000332A (es) 2003-12-11
DOP2002000512A (es) 2003-05-31
WO2003045394A1 (fr) 2003-06-05
GT200200236A (es) 2003-06-25
JP2005513032A (ja) 2005-05-12
CA2468705A1 (fr) 2003-06-05
AU2002341327A1 (en) 2003-06-10
TW200300345A (en) 2003-06-01
KR20040066140A (ko) 2004-07-23
ES2258652T3 (es) 2006-09-01
RU2004116311A (ru) 2005-03-27
PA8559401A1 (es) 2004-02-07
PL374325A1 (en) 2005-10-17
EP1461040A1 (fr) 2004-09-29
JP4196829B2 (ja) 2008-12-17
BR0214559A (pt) 2007-03-13
CN1589148A (zh) 2005-03-02
US20030149044A1 (en) 2003-08-07
PE20030738A1 (es) 2003-08-28
ZA200402720B (en) 2005-05-18
DE60209929D1 (de) 2006-05-11
ATE320256T1 (de) 2006-04-15
UY27548A1 (es) 2003-06-30
SV2004001413A (es) 2004-05-07
AR037677A1 (es) 2004-12-01
US6794388B2 (en) 2004-09-21
IL161326A0 (en) 2004-09-27

Similar Documents

Publication Publication Date Title
EP1461040B1 (fr) Sels succiniques de 5,8,14-triazatetracyclo 10.3.1.02,11.0 4,9 -hexadeca-2(11),3,5,7,9-pentaene et compositions pharmaceutiques associees
US7265119B2 (en) Tartrate salts of 5,8,14-triazatetracyclo[10.3.1.02,11.04.9]-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
US5302599A (en) Therapeutically useful heterocyclic indole compounds
AU2002253482A1 (en) Tartrate salts of 5,8,14-triazatetracyclo (10.3.102,11.04.9)-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
US6787549B2 (en) Citrate salt of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
AU2017208119B2 (en) 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine dopamine D3 ligands
US7094930B2 (en) Pharmaceutically acceptable salts of sertraline and pharmaceutical compositions thereof
NZ250580A (en) 3-(hetero)aryloxymorphinan derivatives and their use in the manufacture of medicaments
EP2496579B1 (fr) 2-azabicyclo[3.1.1]heptyl dérivés 1-substitués utiles en tant que modulateurs du récepteur nicotinique d&#39;acétylcholine pour traiter des troubles neurologiques
EP1451202B1 (fr) Composes azapolycycliques a fusion aryle
EP1638971B1 (fr) Preparation de quinoxalines substituees a partir de la dianiline avec du 2,3-dihydroxy-1,4-dioxane
AU2002255219A1 (en) The citrate salt of 5, 8, 14-triazatetracyclo(10.3.1.02,11,04.9)-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040629

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20050303

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20060315

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

Ref country code: LI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

Ref country code: CH

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60209929

Country of ref document: DE

Date of ref document: 20060511

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060615

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060615

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060615

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060816

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20060315

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2258652

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

ET Fr: translation filed
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20061031

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20061218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060616

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20061021

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060315

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20080915

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20081031

Year of fee payment: 7

Ref country code: IE

Payment date: 20081016

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20081023

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20081016

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20081006

Year of fee payment: 7

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20100630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091102

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100501

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091021

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091021

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20110307

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091021

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110304

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091022